Surgical starting time of the day and survival in gastric cancer

Previous studies indicate differences in short-term postoperative outcomes depending on the surgical starting time of the day, but long-term data are lacking. The aim of this study was to clarify if surgical starting time of the day influences long-term survival in gastric cancer patients. This cohort study consecutively included 2728 patients who underwent curatively intended gastrectomy for gastric cancer in 2011–2015 at a high-volume hospital in China, with follow-up until June 2019. Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for 3-year all-cause mortality, adjusted for age, sex, health insurance, pathological tumor stage, surgical approach, neoadjuvant therapy, and weekday of surgery. Compared with patients with early starting time of gastrectomy (08:00–09:29), the point estimates for 3-year all-cause mortality were modestly increased in patients with a starting time in the middle of day (09:30–13:29; HR 1.15, 95% CI 0.97 to 1.37) and later (13:30–21:25; HR 1.10, 0.91 to 1.32). The corresponding HRs were increased particularly in patients who underwent laparoscopic gastrectomy (HR 1.54, 1.10 to 2.14 and HR 1.59, 1.12 to 2.25, respectively) and in those with stage II tumors (HR 1.74, 1.11 to 2.73 and HR 1.60, 1.00 to 2.58, respectively). Our study indicated that in patients who underwent laparoscopic gastrectomy and in those who with stage II tumors, starting surgery in the early morning might be associated with better long-term survival.

Exposure. The study exposure was the starting time of first incision for gastrectomy, which was extracted as a structural characteristic from the anesthesiology charts in the EMR system. Patients received curativelyintended gastrectomies by a total of 16 (Table S1).
Outcomes. The primary outcome was 3-year all-cause mortality. The 3-year cut-off was chosen instead of 5 years for three reasons: (1) The 3-year mortality mirrors longer term survival, (2) the clinical follow-up practice in the center, and (3) it was possible to follow all patients in the cohort for 3 years within the study period. Data on 3-year all-cause mortality were collected from the patients' medical records or via telephone follow-up (every 3 months for the first 2 years and every 6 months the third year). Secondary outcomes were total number of retrieved lymph nodes and length of postoperative hospital stay. These data were extracted directly from the medical records and pathology reports. Statistical analysis. The patients were followed up from the date of gastrectomy until the end of study or death, whichever occurred first. The association between surgical starting time of the day and 3-year allcause mortality was assessed using multivariable Cox proportional hazards regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs). Seven predefined covariates were included in a multivariable model because of their known prognostic influence in combination with possible influence on the surgical starting time of the day: (1) age at surgery (continuous), (2) sex (male or female), (3) health insurance coverage (yes or no), (4) neoadjuvant therapy (yes or no), (5) pathological tumor stage (0-I, II, or III), and (6) surgical approach (open, laparoscopic or robotic), and (7) weekday of surgery (Monday-Wednesday or Thursday-Friday). The  www.nature.com/scientificreports/ proportional hazards assumption was tested by Schoenfeld residuals and was met in all analyses. To explore associations within specific subgroups, analyses were stratified by the aforementioned 7 covariates using the same categorization, as well as by Charlson comorbidity (0, 1, or ≥ 2) and tumor location (cardia or non-cardia). Survival curves for different surgical starting time groups were generated using Kaplan-Meier estimates and compared by the log-rank test. The secondary outcomes, i.e. postoperative stay and number of retrieved lymph nodes, were both treated as binary variables with the cut-off set at the median values, i.e. 11 days of postoperative stay and 23 lymph nodes. The association between surgical starting time of the day and these outcomes was assessed using multivariable logistic regression, providing odds ratios (ORs) with 95% CIs, adjusted for the seven covariates (with the same categorization) presented above.
All statistical analyses followed a detailed pre-defined study protocol and were performed by first author (YG) and checked by an experienced statistician (FM) using the SPSS software, version 25 (SPSS Inc, Chicago, IL). All tests were 2-sided and statistical significance was set at P < 0.05.

Patients.
A total of 2728 patients who underwent planned and curatively intended gastrectomy for gastric cancer were included in the cohort. Most patients were men (2065, 75.7%) and the median age was 60 years (interquartile range 52-67). There were no major differences in the distribution of age, sex, tumor location, pathological tumor stage, comorbidity, or neoadjuvant therapy among the three surgical starting time groups, but there was a trend of more self-paid patients in the two later surgical starting time groups compared to the early group ( Table 1). The distribution of surgical approach, reconstruction method, and extent of the lymph node dissection was similar in the three surgical starting time groups ( Table 2). The patients were followed up   3-year all-cause mortality. The 3-year all-cause mortality rate was 26.0% in the entire cohort and no major differences were observed among the three surgical starting time groups in crude analysis (Fig. 2a,  Lymph node retrieval and length of postoperative stay. Gastrectomy performed later during the day was not associated with obvious increased odds of lymph node retrieval (

Discussion
This study indicated an increased risk of 3-year all-cause mortality in gastric cancer patients if the surgical starting time was later in the day than in the early morning, particularly in those who underwent laparoscopic gastrectomy and with pathological stage II tumor. The surgical starting time during the day did not influence the lymph node yield or length of postoperative hospital stay. Some methodological issues need to be discussed in order to interpret the findings. First, it was not feasible to randomly assign the surgical starting time of the day, which left us with an observational design. Second, this study was based on one of the largest cancer centers in China and focused on gastric cancer, thus providing a large sample size and counteracting disease heterogeneity. The single-center high-volume approach also allowed complete and detailed clinical data and at least partly counteracted bias resulting from different surgeon volumes. On the other hand, the results from this single center might be less generalizable. Third, the assessment of the gastrectomy starting time (exposure), 3-year all-cause mortality (main outcome) and covariates was objective and accurate. The surgery day rotation system at the center enabled each consultant surgeon to have similar opportunities to arrange their operation schedule, meaning that factors like age or experience of the surgeon would not influence the surgical starting time. However, due to lack of data on cause-specific death, we could not assess disease-specific mortality. Fourth, potential confounding by the main prognostic factors was carefully adjusted for in the analyses, but residual confounding cannot be ruled out.
To the best of our knowledge, this is the first study examining the role of 'time of the day' variations in surgery in relation to long-term survival in gastric cancer. The finding that gastric cancer patients who underwent www.nature.com/scientificreports/ laparoscopic surgery and those diagnosed with pathological tumor stage II tended to have worse survival if the gastrectomy was started later in the day is interesting. Chance cannot be excluded as an explanation, but the findings may also be true. Speculatively, the workload accumulation during the day might influence the performance of the surgeons and the surgical team 21,22 . This could be more of an issue for laparoscopic surgery than for open surgery, because laparoscopic procedures tend to be more time-consuming and technically demanding 23,24 . However, statistically differences were not observed in robotic assisted gastrectomy. We speculated that limited sample size of robotic surgery might mainly account for this finding, which calls for  www.nature.com/scientificreports/ further studies with larger cohort of robotic surgeries to address. A possible explanation for the tumor stage II-specific finding is a that the fine-tuning of the surgical accuracy may be less critical in patients with earlier tumor stage who usually have a very high survival rate anyway, while those with more advanced tumors more often have invisible tumor spread beyond surgical cure 25,26 . Patients with stage II tumors, on the other hand, may benefit most from the best possible surgical treatment. The absence of better survival in the middle starting group than that the last starting group may speculatively be due to the fact that surgeons did not get a break or any food before starting surgery around lunch time. Because lymphadenectomy 27,28 and postoperative complications and re-operations might influence the longterm survival 29,30 , we explored the surgical starting time during the day in relation to lymph node retrieval and length of hospital stay. The lack of associations with these outcomes indicate that these factors were not mediators of the worse survival in gastric cancer patients who underwent surgery later in the day.
The findings from this first study examining the topic need confirmation in future research before any clinical implications can be considered. Large population-based studies examining a more detailed grouping of the surgical starting time may be particularly useful in this respect. If proven true, these results indicate a need to tailor the starting time of gastrectomy. Although this study focused on surgery for gastric cancer, it is possible that similar mechanism and results might be generalizable to other challenging surgical cancer procedures, for example, surgery for colorectal, hepatobiliary and pancreatic cancers.

Conclusions
In conclusion, this current study indicated that in patients with gastric cancer, especially those who undergo laparoscopic gastrectomy and those diagnosed with stage II tumors, initiating surgery in the early morning was possibly associated with better prognosis, which still needs further prospective clinical trials to verify.

Data availability
The anonymous data during the current study are available from the corresponding author upon reasonable request.